Efficacy and Safety of RAD001 in Treating Plexiform Neurofibromas (PN) Associated With Neurofibromatosis (NF1)
Study Details
Study Description
Brief Summary
This study was to evaluate the antitumor activity and safety of RAD001 in patients with Plexiform neurofibromas (PN) associated with Neurofibromatosis Type 1 (NF1).
The aim of the study was to :
-
determine whether RAD001, administrated orally daily on a continuous dosing schedule might:
-
Increases time to disease progression (TTP) based on volumetric MRI measurements in children and adults with NF1 in inoperable documented progressive PN (stratum 1).
-
Results in objective radiographic responses based on volumetric MRI measurements in children and adults with NF1 and inoperable PN in the absence of documented radiographic progression at the trail entry (stratum
-
To evaluate the tolerability and toxicity of chronic RAD001 administration in this patient population as assessed by the NCI Common Toxicity Criteria, version 4.0.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
Approximately 20 patients were to be enrolled to receive everolimus in an open label manner. A total of 9 patients were enrolled to either Stratum 1 or Stratum 2.
The study was open for enrollment up to 2 years. Because the target enrollment was not achieved in this period, study was terminated with less patient than planned.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Everolimus (RAD001) enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. |
Drug: Everolimus (RAD001)
oral daily dosing of tablet starting with 2.5 mg
|
Outcome Measures
Primary Outcome Measures
- Time to Disease Progression (TTP) Based on Change in Volumetric MRI Measurements in Children and Adults (In Stratum I Only) [Screening, after course #6, #12, #18, #24, End of Treatment(1 course=28days)]
This endpoint was planned to be analyzed for only Stratum 1 patients. Progression of disease defined as a ≥ 20% increase in the volume (by volumetric MRI) of at least one of the index plexiform neurofibromas (PN) compared to the pretreatment volume measured prior to the start of the current treatment phase.
- Number of Patients With Objective Radiographic Responses Based on Volumetric MRI Measurements (In Stratum 2 Only) [Screening, after course #6, then every 6 months and end of treatment(1 course=28days)]
Response was assessed at the time that a follow up volumetric MRI scan is performed (after course 6 and then every 6 months and at the end of treatment). Complete response (CR): complete resolution of all measurable or palpable PN for ≥ 28days and no appearance of new lesions. Partial response (PR): A ≥ 20% reduction in the sum of the volume of all index PN lesions for ≥ 28days. Stable disease (SD): A < 20% increase and < 20% decrease in the sum of the volume of all index PN lesions for ≥ 28days.
- Number of Patients With Adverse Events Assessed by Common Toxicity Criteria for Adverse Events (CTCAE) V.04 [From the time ICF was signed until 28 days after End of Treatment (up to a maximum of 25 months)]
Adverse events were assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0. If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, and life-threatening, corresponding to grades 1 - 4 respectively, were used. CTCAE grade 5 (death) was not used in this study.
Other Outcome Measures
- Number of Patients With Clinical Response [Screening, Day 1, after course #3, #6, #12, #18, #24, End of Treatment (1 course = 28 days)]
Clinical response is defined as improvement of function, performance status, or decrease in PN related pain persisting for at least 28 days on treatment.
- Physician's Global Assessment of Clinical Condition (PGA) of Skin Lesions [Screening, after course #3, #6, #12, #18, #24, End of Treatment (1 course = 28 days)]
The Physician"s Global Assessment of Clinical Condition (PGA) is a 7-point grading scale for the investigator's assessment of the overall extent of improvement or worsening of the patient"s skin disease as compared to baseline. Responses must be confirmed by at least two assessments separated in time by at least 4 weeks. The grading ranges from 0 to 6; 0 is Completely clear where as 6 is for worse condition. A complete clinical response (CCR) requires a grading of 0 indicating the absence of disease (histological confirmation is not required). Grades 1, 2, and 3 constitute partial response, indicating improvement of at least 50 percent, but less than 100 percent improvement.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Clinically definite diagnosis of NF1 according to the NIH consensus conference criteria.
-
Patients must have PN that have the potential to cause significant morbidity, such as lesions that could compromise the airway or the great vessels, lesions that could cause nerve compression, lesions that could result in major deformity or significant cosmetic problems
-
Measurable disease: patient must have at least one measurable PN amenable to volumetric MRI analysis.
Exclusion Criteria:
-
Chronic treatment with systemic steroids or another immunosuppressive agent.
-
Evidence of an active optic glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiation therapy.
-
Clinical evidence of significantly impaired lung function
-
Pregnancy or breast feeding.
-
Prior therapy with mTOR inhibitors (e.g.sirolimus, temsirolimus, everolimus).
-
No contraindications for MRI assessments
Other protocol-defined inclusion/exclusion criteria may apply
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Novartis Investigative Site | Tel-Aviv | Israel | 6423906 | |
| 2 | Novartis Investigative Site | Tel-Hashomer | Israel | 52621 |
Sponsors and Collaborators
- Novartis Pharmaceuticals
Investigators
- Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CRAD001MIL04T
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Stratum 1 | Stratum 2 |
|---|---|---|
| Arm/Group Description | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity with documented progressive PN prior to study entry wereenrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity that do not have documented progression of the PN at the time of study entry were enrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. |
| Period Title: Overall Study | ||
| STARTED | 4 | 5 |
| COMPLETED | 0 | 5 |
| NOT COMPLETED | 4 | 0 |
Baseline Characteristics
| Arm/Group Title | Stratum 1 | Stratum 2 | Total |
|---|---|---|---|
| Arm/Group Description | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity with documented progressive PN prior to study entry wereenrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity that do not have documented progression of the PN at the time of study entry were enrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. | Total of all reporting groups |
| Overall Participants | 4 | 5 | 9 |
| Age (Years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [Years] |
22.7
(14.3)
|
16.9
(9.8)
|
19.5
(11.6)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
3
75%
|
1
20%
|
4
44.4%
|
| Male |
1
25%
|
4
80%
|
5
55.6%
|
Outcome Measures
| Title | Time to Disease Progression (TTP) Based on Change in Volumetric MRI Measurements in Children and Adults (In Stratum I Only) |
|---|---|
| Description | This endpoint was planned to be analyzed for only Stratum 1 patients. Progression of disease defined as a ≥ 20% increase in the volume (by volumetric MRI) of at least one of the index plexiform neurofibromas (PN) compared to the pretreatment volume measured prior to the start of the current treatment phase. |
| Time Frame | Screening, after course #6, #12, #18, #24, End of Treatment(1 course=28days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) consisted of all enrolled patients. |
| Arm/Group Title | Stratum 1 |
|---|---|
| Arm/Group Description | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity with documented progressive PN prior to study entry wereenrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. |
| Measure Participants | 4 |
| Median (95% Confidence Interval) [Days] |
NA
|
| Title | Number of Patients With Objective Radiographic Responses Based on Volumetric MRI Measurements (In Stratum 2 Only) |
|---|---|
| Description | Response was assessed at the time that a follow up volumetric MRI scan is performed (after course 6 and then every 6 months and at the end of treatment). Complete response (CR): complete resolution of all measurable or palpable PN for ≥ 28days and no appearance of new lesions. Partial response (PR): A ≥ 20% reduction in the sum of the volume of all index PN lesions for ≥ 28days. Stable disease (SD): A < 20% increase and < 20% decrease in the sum of the volume of all index PN lesions for ≥ 28days. |
| Time Frame | Screening, after course #6, then every 6 months and end of treatment(1 course=28days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) consisted of all enrolled patients. |
| Arm/Group Title | Stratum 2 |
|---|---|
| Arm/Group Description | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity that do not have documented progression of the PN at the time of study entry were enrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. |
| Measure Participants | 5 |
| Complete Response |
0
|
| Partial Response |
0
|
| Stable Disease |
5
|
| Title | Number of Patients With Adverse Events Assessed by Common Toxicity Criteria for Adverse Events (CTCAE) V.04 |
|---|---|
| Description | Adverse events were assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0. If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, and life-threatening, corresponding to grades 1 - 4 respectively, were used. CTCAE grade 5 (death) was not used in this study. |
| Time Frame | From the time ICF was signed until 28 days after End of Treatment (up to a maximum of 25 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Safety Population consisted of all patients who received at least one dose of study treatment and had at least one post-baseline safety assessment. |
| Arm/Group Title | Stratum 1 | Stratum 2 |
|---|---|---|
| Arm/Group Description | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity with documented progressive PN prior to study entry wereenrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity that do not have documented progression of the PN at the time of study entry were enrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. |
| Measure Participants | 4 | 5 |
| At least one Grade 1 AE |
4
|
5
|
| At least one Grade 2 AE |
4
|
5
|
| At least one Grade 3 AE |
1
|
0
|
| At least one Grade 4 AE |
1
|
0
|
| Title | Number of Patients With Clinical Response |
|---|---|
| Description | Clinical response is defined as improvement of function, performance status, or decrease in PN related pain persisting for at least 28 days on treatment. |
| Time Frame | Screening, Day 1, after course #3, #6, #12, #18, #24, End of Treatment (1 course = 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Study got terminated because of poor patient's accrual. Enrolled patients were less than planned number of patients required for analysis. Hence, planned analysis was not done. |
| Arm/Group Title | Stratum 1 | Stratum 2 |
|---|---|---|
| Arm/Group Description | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity with documented progressive PN prior to study entry wereenrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity that do not have documented progression of the PN at the time of study entry were enrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. |
| Measure Participants | 0 | 0 |
| Title | Physician's Global Assessment of Clinical Condition (PGA) of Skin Lesions |
|---|---|
| Description | The Physician"s Global Assessment of Clinical Condition (PGA) is a 7-point grading scale for the investigator's assessment of the overall extent of improvement or worsening of the patient"s skin disease as compared to baseline. Responses must be confirmed by at least two assessments separated in time by at least 4 weeks. The grading ranges from 0 to 6; 0 is Completely clear where as 6 is for worse condition. A complete clinical response (CCR) requires a grading of 0 indicating the absence of disease (histological confirmation is not required). Grades 1, 2, and 3 constitute partial response, indicating improvement of at least 50 percent, but less than 100 percent improvement. |
| Time Frame | Screening, after course #3, #6, #12, #18, #24, End of Treatment (1 course = 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Study got terminated because of poor patient's accrual. Enrolled patients were less than planned number of patients required for analysis. Hence, planned analysis was not done. |
| Arm/Group Title | Stratum 1 | Stratum 2 |
|---|---|---|
| Arm/Group Description | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity with documented progressive PN prior to study entry wereenrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity that do not have documented progression of the PN at the time of study entry were enrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. |
| Measure Participants | 0 | 0 |
Adverse Events
| Time Frame | ||||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Stratum 1 | Stratum 2 | ||
| Arm/Group Description | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity with documented progressive PN prior to study entry wereenrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity that do not have documented progression of the PN at the time of study entry were enrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. | ||
All Cause Mortality |
||||
| Stratum 1 | Stratum 2 | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Stratum 1 | Stratum 2 | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/4 (25%) | 0/5 (0%) | ||
| Immune system disorders | ||||
| Hypersensitivity | 1/4 (25%) | 0/5 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Stratum 1 | Stratum 2 | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 4/4 (100%) | 5/5 (100%) | ||
| Ear and labyrinth disorders | ||||
| Ear pain | 2/4 (50%) | 0/5 (0%) | ||
| External ear inflammation | 0/4 (0%) | 1/5 (20%) | ||
| Eye disorders | ||||
| Ocular hyperaemia | 1/4 (25%) | 0/5 (0%) | ||
| Gastrointestinal disorders | ||||
| Abdominal pain | 1/4 (25%) | 2/5 (40%) | ||
| Diarrhoea | 2/4 (50%) | 0/5 (0%) | ||
| Dysphagia | 2/4 (50%) | 0/5 (0%) | ||
| Flatulence | 0/4 (0%) | 1/5 (20%) | ||
| Mouth ulceration | 0/4 (0%) | 1/5 (20%) | ||
| Nausea | 1/4 (25%) | 0/5 (0%) | ||
| Stomatitis | 0/4 (0%) | 1/5 (20%) | ||
| Toothache | 1/4 (25%) | 1/5 (20%) | ||
| Vomiting | 1/4 (25%) | 1/5 (20%) | ||
| General disorders | ||||
| Asthenia | 0/4 (0%) | 1/5 (20%) | ||
| Chest pain | 1/4 (25%) | 0/5 (0%) | ||
| Discomfort | 1/4 (25%) | 0/5 (0%) | ||
| Fatigue | 2/4 (50%) | 2/5 (40%) | ||
| Influenza like illness | 3/4 (75%) | 1/5 (20%) | ||
| Mucosal inflammation | 2/4 (50%) | 2/5 (40%) | ||
| Oedema peripheral | 1/4 (25%) | 0/5 (0%) | ||
| Pain | 1/4 (25%) | 1/5 (20%) | ||
| Peripheral swelling | 1/4 (25%) | 0/5 (0%) | ||
| Infections and infestations | ||||
| Eye infection | 0/4 (0%) | 1/5 (20%) | ||
| Pneumonia | 0/4 (0%) | 1/5 (20%) | ||
| Skin infection | 0/4 (0%) | 1/5 (20%) | ||
| Injury, poisoning and procedural complications | ||||
| Tendonitis | 1/4 (25%) | 0/5 (0%) | ||
| Investigations | ||||
| Blood cholesterol increased | 1/4 (25%) | 2/5 (40%) | ||
| Blood creatine phosphokinase increased | 0/4 (0%) | 1/5 (20%) | ||
| Blood triglycerides increased | 1/4 (25%) | 1/5 (20%) | ||
| Drug level increased | 1/4 (25%) | 0/5 (0%) | ||
| Eosinophil count increased | 0/4 (0%) | 1/5 (20%) | ||
| Low density lipoprotein increased | 1/4 (25%) | 0/5 (0%) | ||
| Lymphocyte count decreased | 1/4 (25%) | 0/5 (0%) | ||
| Platelet count decreased | 1/4 (25%) | 1/5 (20%) | ||
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 1/4 (25%) | 1/5 (20%) | ||
| Hypertriglyceridaemia | 1/4 (25%) | 1/5 (20%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal chest pain | 1/4 (25%) | 0/5 (0%) | ||
| Pain in extremity | 2/4 (50%) | 0/5 (0%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Fibroma | 1/4 (25%) | 0/5 (0%) | ||
| Nervous system disorders | ||||
| Dizziness | 1/4 (25%) | 1/5 (20%) | ||
| Headache | 3/4 (75%) | 4/5 (80%) | ||
| Paraesthesia | 1/4 (25%) | 0/5 (0%) | ||
| Psychiatric disorders | ||||
| Anxiety | 0/4 (0%) | 1/5 (20%) | ||
| Insomnia | 0/4 (0%) | 1/5 (20%) | ||
| Sleep disorder | 0/4 (0%) | 1/5 (20%) | ||
| Tic | 1/4 (25%) | 0/5 (0%) | ||
| Reproductive system and breast disorders | ||||
| Breast mass | 1/4 (25%) | 0/5 (0%) | ||
| Metrorrhagia | 1/4 (25%) | 0/5 (0%) | ||
| Vaginal haemorrhage | 1/4 (25%) | 0/5 (0%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Dysphonia | 0/4 (0%) | 1/5 (20%) | ||
| Dyspnoea | 1/4 (25%) | 0/5 (0%) | ||
| Oropharyngeal pain | 1/4 (25%) | 2/5 (40%) | ||
| Pharyngeal erythema | 1/4 (25%) | 0/5 (0%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Alopecia | 0/4 (0%) | 1/5 (20%) | ||
| Dermatitis acneiform | 0/4 (0%) | 1/5 (20%) | ||
| Rash | 2/4 (50%) | 0/5 (0%) | ||
| Surgical and medical procedures | ||||
| Cytoreductive surgery | 0/4 (0%) | 1/5 (20%) | ||
| Tooth extraction | 0/4 (0%) | 1/5 (20%) | ||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
Results Point of Contact
| Name/Title | Study Director |
|---|---|
| Organization | Novartis Pharmaceuticals |
| Phone | 862-778-8300 |
| trialandresults.registries@novartis.com |
- CRAD001MIL04T